Calcium-Ion Binding Mediates the Reversible Interconversion of Cis and Trans Peroxido Dicopper Cores

Article abstract of DOI:10.1002/anie.202105421

Coupled dinuclear copper oxygen cores (Cu₂O₂) featured in type III copper proteins (hemocyanin, tyrosinase, catechol oxidase) are vital for O₂ transport and substrate oxidation in many organisms. μ-1,2-cis peroxido dicoppe

Full text of DOI:10.1002/anie.202105421

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Accepted Article
Title: Calcium-ion Binding Mediates the Reversible Interconversion of
Cis and Trans Peroxido Dicopper Cores
Authors: Natasha P. Vargo, Jill B Harland, Bradley W Musselman,
Nicolai Lehnert, Mehmed Zahid Ertem, and Jerome Ronald
Robinson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202105421
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Calcium-ion Binding Mediates the Reversible Interconversion of
Cis and Trans Peroxido Dicopper Cores
Natasha P. Vargo,[a] Jill B. Harland,[b] Bradley W. Musselman,[b] Nicolai Lehnert,[b]* Mehmed Z.
Ertem,[c]* Jerome R. Robinson[a]*
Abstract: Coupled dinuclear copper oxygen cores (Cu2O2) featured
in type III copper proteins (e.g. hemocyanin, tyrosinase, catechol
oxidase) are vital for O2 transport and substrate oxidation in a range
of organisms. μ-1,2-cis peroxido dicopper cores (CP) have been
proposed as key structures involved in the early stages of O2 binding
in these proteins, and their reversible isomerization to other Cu2O2
cores are directly relevant to enzyme function. Despite the relevance
of such species to type III copper proteins and the broader interest in
the properties and reactivity of bimetallic CP cores in biological and
synthetic systems, the properties and reactivity of CP Cu2O2 species
remain largely unexplored. Herein, we report our combined synthetic,
spectroscopic, and theoretical studies which detail the first reversible
interconversion of μ-1,2-trans peroxido (TP) and CP dicopper cores.
Figure 1. (a) Commonly observed O2 binding modes found in Cu2O2 cores,
CaII mediates this process through reversible binding at the Cu2O2
and direct equilibria established in experimental systems. (b) Proposed
species involved in O2 binding at hemocyanin (Hc). (c) Reversible NaI binding
to a CP Cu2O2 core.7j (d) Sc(OTf)3 mediated reversible interconversion of
SP/O.22b (e) This work: Reversible interconversion of TP/CP (1/2) mediated by
Ca(OTf)2.
core, and highlights the unique capability for metal-ion binding events
to stabilize novel reactive fragments and control O2 activation in
biomimetic systems.
multi-copper enzymes (Figure 1b).[15] Formation of CP at type III
active sites enables simultaneous electron transfer from the two
CuI sites, and the reversible interconversion of the weakly coupled
CP species to strongly (antiferromagnetically) coupled SP species
is central to enzyme function. More broadly, CP structures are
relevant intermediates in the oxygenation chemistry of other first-
row transition metal ions (e.g. Co and Fe),[16] including the
bimetallic active sites of soluble methane monooxygenase and
ribonucleotide reductase.[17] Despite the importance of such
structures and their interconversion chemistry, CP Cu2O2 cores
remain largely unexplored.[7j,14]
Copper containing enzymes such as hemocyanin,[1]
tyrosinase,[2] catechol oxidase,[3] and particulate methane
monooxygenase[4] feature a variety of reactive oxygen species
that
range
in
function
from
O2
transport,
C–H
oxidation/functionalization, and reduction of O2 to water.[5] These
enzymes have inspired numerous synthetic models[6] which have
advanced our understanding of biological systems,[5c,6-7]
alongside applications in catalysis,[8] materials science,[9] and
renewable energy.[10] Amongst these copper oxygen species,
dicopper oxygen (Cu2O2) cores are ubiquitous in both biological
and synthetic systems, where Cu2O2 cores display dramatically
different reactivity and properties depending on their binding
mode (Figure 1a). While examples of μ-1,2-trans peroxido (end-
on; TP),[7c,11] η2:η2 peroxido (side-on; SP),[7a,7b,12] bis(μ-oxido)
(O),[7e,12g,13] structures are now well established, models of the μ-
1,2-cis peroxido (CP) or distorted CP Cu2O2 core are exceedingly
rare and have only recently been achieved using ancillary ligands
specifically designed to constrain Cu–Cu distances to access this
binding mode.[7j,14]
Redox-inactive metal ions serve critical roles as natural[18] and
synthetic[19] co-factors for the activation or production of oxygen
at transition-metal complexes. Lewis acid binding events can
stabilize and modulate the reactivity of novel O2-derived
fragments,[20],[7j,20c,21] yet few studies have centered on the
reactivity of Cu2O2 cores.[7j,22] Meyer and coworkers reported the
first synthetic Cu2O2 CP core, [CuII (PzTACNMe)(μ-1,2-O22-)]+
2
(Figure 1c).[7j] NaI reversibly binds at the peroxido fragment;
however, minimal structural changes were observed due to the
rigidity of the binucleating chelate (Figure 1c). Karlin and
coworkers reported that addition of Sc(OTf)3 mediated the
reversible interconversion of {[CuII(MeAN)]2(η2:η2-O22-)}2+ (SP;
MeAN: N-methyl-N,N-bis[3-(dimethylamino)propyl]amine) to
[CuIII2(MeAN)2(μ-O)2]2+ (O) by promoting dissociation of the
axially-bound tertiary amine donor (Figure 1d).[22b] Karlin and
Fukuzumi observed that the prototypical TP species,
{[CuII(TMPA)]2(μ-1,2-O22-)}2+ (TMPA = tris(2-pyridylmethyl)amine)
(1), reacts with Sc(OTf)3 in acetone at –80 °C to generate a
transient intermediate believed to be responsible for the catalytic
peroxide-selective reduction of oxygen (λmax = 394 nm); however,
its limited lifetime precluded further characterization.[22a]
Solomon and coworkers proposed the CP Cu2O2 core as a key
structure in the early stages of reversible O2 binding at type III
[a]
N. P. Vargo, Prof. J. R. Robinson
Department of Chemistry
Brown University
324 Brook Street, Providence, RI 02912, USA
E-mail: jerome_robinson@brown.edu
J. B. Harland, B. W. Musselman, Prof. N. Lehnert
Department of Chemistry and Department of Biophysics
University of Michigan
[b]
[c]
930 North University Avenue, Ann Arbor, MI, 41809-1055, USA
Dr. M. Z. Ertem
Chemistry Division, Energy & Photon Sciences
Brookhaven National Laboratory
PO Box 5000, Upton, NY, 11973-5000, USA
We were especially intrigued by the rapid reactivity of 1 with
Sc(OTf)3, as this implies that the Cu2O2 core is flexible enough to
Supporting information for this article is given via a link at the end of
the document.
reorganize and interact with
a redox-inactive metal ion.
1
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Recognizing the importance of matching Lewis acid strength and
size to support reactive transition-metal fragments, we
hypothesized that weaker Lewis acids could stabilize otherwise
transient heterobimetallic species through direct binding at the
peroxido fragment while reducing the driving force for complete
dissociation. Herein, we report our combined synthetic,
spectroscopic, and theoretical studies which detail the first
reversible interconversion of the prototypical TP, 1, to a novel CP
species, 2 (Figure 1e). This process is mediated through
reversible CaII ion binding to the Cu2O2 core, and our observed
reactivity contrasts with that of 1 with stronger Lewis acids (e.g.
Sc(OTf)3) or Brønsted acids (e.g. TFA, HClO4). These results
highlight the unique capability for metal-ion binding events to
stabilize novel reactive fragments and control O2 activation in
biomimetic systems.
At –80 °C, freshly prepared acetone solutions of dark purple 1
(0.25 mM; t1/2 = 150 s) react with excess Ca(OTf)2 (5 mM) within
seconds to form a bright yellow species, 2 (Figure 2a; t1/2 = 285 s;
λmax = 455 nm, ε = 4080 M-1 cm-1) without accumulation of
observable intermediates and displays a clean isosbestic point at
490 nm. The charge transfer band position and molar absorptivity
of 2 are comparable to those found for μ-1,2- peroxido dicopper
cores supported by TMPA frameworks with hydrogen bond
donors in the 6-position [e.g. NH2,[23] NHAr;[11e] λmax ~ 450 nm (є =
2,400 – 4,620 M-1 cm-1)]. Similar reactivity and spectroscopic
signatures were observed upon addition of Ca(ClO4)2 to 1 in place
of Ca(OTf)2, albeit with incomplete conversion and lower product
thermal stability (Figure S14). In contrast, addition of excess free
triflate to 1 ([NBu4][OTf], 20 equiv; Figure S10) caused negligible
changes in its electronic absorbance spectrum, and further
confirmed that formation of 2 was the result of CaII binding. While
thermally-sensitive, concentrated acetone solutions of 2 (≥ 2 mM)
are stable at –80 °C for weeks in the absence of excessive
moisture, which facilitated further spectroscopic characterization.
Resonance Raman (rRaman) spectroscopy (77 K; λex = 457
nm; Figure 2b) was performed on frozen acetone glasses of 1 and
2 prepared with 16O2 and 18O2. The rRaman spectrum of 2
revealed a single isotopically-sensitive vibration at 812 cm-1 (vO–
O; Δ16O2–18O2 = –43 cm-1) that was red-shifted by ~18 cm-1 relative
to 1 (vO–O(1): 830 cm-1; Δ16O2–18O2 = –45 cm-1). vO–O(2) falls within
the characteristic range of TP and CP dicopper species (800–850
cm-1), but well outside the range of mononuclear superoxido or
peroxido (η1 or η2: 960–1150 cm-1), μ-η2:η2 (side-on, SP) peroxido
dicopper (vO–O: 715–730 cm-1), and 1,1-hydroperoxido dicopper
(vO–O: 860–880 cm-1).[6c,20b,24] Lewis acid binding at peroxido
fragments have led to red-shifted vO–O (~5–30 cm-1), although the
magnitude of this shift is sensitive to Lewis acid strength and
complex geometry.[7j,21a,21e,25] Taken together, we hypothesized
the distinct spectroscopic changes going from 1 to 2 (blue-shifted
LMCT λmax, red-shifted vO–O) was due to CaII binding to the
peroxido fragment of 1, and prompted further structural
investigation.
Figure 2. (a) Selected electronic absorbance spectra following the addition
of CaII(OTf)2 (5 mM) to 1 (0.5 mM, purple trace) in acetone at –80 °C to form
2 (gold trace, time = 20 s). (b) rRaman spectra (λex = 456.8 nm) of 1 (purple)
and 2 (gold) in acetone at 77 K (top = 16O2, bottom = 18O2). * = vCF3 (OTf);
796 cm-1 and # = vC–C (Acetone); 870 cm-1.
revealed rapid association and dissociation of CaII at –80 °C,
where the forward (k+) and reverse (k–) rate-constants were
determined to be 2.71 ± 0.25 x 102 M-1s-1 and 0.22 ± 0.02 s-1,
respectively. Addition of 18-crown-6 (18-C-6) to 2 ([Ca]:[18-C-6] =
1:2) cleanly regenerates 1 within ~10 seconds at –80 °C, clearly
demonstrating that interconversion of 1 and 2 is both rapid and
Figure 3. (a) Proposed interconversion between 1 and 2 using CaII(OTf)2 and
18-C-6 chelate (0 - 10 s). Ac = acetone, n = 3 or 4; (b) Titration of CaII (guest)
to 1 (host, purple; circles) to form 2 (gold; diamonds), inset: association
constant (KCaII), forward (k+) and reverse (k–) kinetic rate constants for CaII
binding (see SI for details). (c) Spectral changes upon 18-C-6 addition (10 mM)
to 2 (0.5 mM; 5 mM Ca(OTf)2) in acetone at –80 °C.
chemically reversible (Figure 3c).
Complex 2 is EPR-silent at X-band frequencies (Figure S20)
and 1H-NMR spectroscopy (Figure S26-28) provided clear
evidence for 2 being paramagnetic. The EPR silence of 2 is
inconsistent with the formation of any mono-copper peroxido
species (including hydro or alkylperoxido), as these would display
strong and distinct signals at X-band frequencies.[27] The 1H-NMR
spectrum of 2 collected in d6-acetone at –80 °C displayed ~15
paramagnetically shifted resonances (–4 to +120 ppm; Figure
S28), and reflected the loss of 3-fold symmetry of the TMPA
ligand. Desymmetrization would be expected for a dicopper
peroxido with hindered rotation about the Cu–O bond, and was
consistent with the tight CaII binding determined from our
spectrophotometric titrations (vide supra).
A reversible 1:1 binding stoichiometry for [1]:[Ca(OTf)2] (Figure
3a) was established from nonlinear regression of multiple
independent titrations with 1 performed at –80 °C across a range
of [1]:[Ca] ratios (1:1–1:20; Figure 3b, S11; see Section 3.4 for
further details).[26] The association constant for the 1:1 binding of
Ca(OTf)2 to 1, KCaII, was determined to be 1,220 ± 70 M-1 and is
Complex 2 has an effective magnetic moment (μeff) of 2.44 μB
as determined by Evans’ method (d6-acetone, –80 °C; Table
S3).[28] The μeff of 2 is significantly greater than 1 or [CuII(TMPA)]2+
(Figure S31), but lower than that expected for two strongly
comparable KNaI (1,770 M-1) observed for [CuII (PzTACNMe)(μ-1,2-
2
O22–)Na(OTf)]+.[7j] Kinetic parameters obtained under flooding
conditions (> 10-fold excess Ca(OTf)2; Figure 3b and Figure S13)
2
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ferromagnetically coupled CuII ions (μeff ~ 2.83 μB).[14,29] This is
wholly inconsistent with a TP Cu2O2 core (φCu2O2 ~180°), which are
EPR silent and display effectively diamagnetic NMR spectra due
to strong antiferromagnetic coupling mediated through the
peroxido bridge (J ≤ –600 cm-1; Figure 4c, right).[11a] In contrast,
the EPR silence and non-zero μeff of 2 is consistent with a CP
Cu2O2 core (φCu2O2→90°). The two reported CP display
paramagnetic NMR spectra and weak magnetic coupling for the
Cu2O2 core (PzTACNMe: φCu2O2 = 62.5°, J = –77 cm-1; PzTACNEt:
φCu2O2 = 104.2°, J = +72 cm-1; H = –2JS1S2)[7j,14] due to interaction
of the CuII dx2 2 orbitals with orthogonal π*(O2) orbitals (Figure 4c,
-y
right). Unfortunately, the thermal sensitivity of 2 has prevented our
experimental
determination
of
J
through
solid-state
1
magnetometry or fitting of variable temperature H-NMR spectra
like other recent bimetallic peroxides,[7j,14,30] but a more detailed
investigation of the electronic structure of 2 is warranted for future
studies.
The reactivity of 1 with Ca(OTf)2 was further substantiated by
computational studies performed at the M06-L level of theory[31]
(Computational Methods; see Supporting Information). Given the
expected speciation of Ca(OTf)2 in acetone based on conductivity
measurements (Figure S32),[32] 1:1 CaII binding to mononuclear
and dinuclear copper peroxido species were explored from
[Ca(OTf)2(Ac)4] and [Ca(OTf)(Ac)5]+ with an exhaustive search of
possible conformers (Scheme S3 and S4). Consistent with our
spectroscopic data (i.e. NMR, UV-Vis), the generation of a
heterobimetallic {[CuII(TMPA)](μ-η1:η2-O22-)[CaII(OTf)x(Ac)n]}2-x+
core (A) and an equivalent of [CuII(TMPA)]2+ is unlikely, where the
reaction is predicted to be endergonic by 14.4 kcal/mol (Figures
S32-S33, Scheme S3). CaII binding to the distal peroxido site of a
2–
1,1-peroxido dicopper core, {[CuII(TMPA)]2(μ-η1:η1:η1-O2
)
Figure 4. (a) Possible heterobimetallic structures from the reaction of 1 with
2–
Ca(OTf)2(Ac)4
(Ac
=
Acetone);
A:
{[CuII(TMPA)](μ-η1:η2-O2
[CaII(OTf)(Ac)4]}3+ (B) is slightly exergonic (–3.9 kcal/mol);
however, this structure is a poor match with experimental data
and literature expectations. Related 1,1-hydroperoxido dicopper
cores display higher vO–O (860-880 cm-1)[33] and strong
antiferromagnetic coupling,[33e,34] both of which are reflected in the
calculated properties of B and its conformers (Figure S33, S34,
Table S4). Alternatively, formation of CP is favored by 9.6 kcal/mol,
and the calculated and experimental rRaman spectra are in
excellent agreement with one another (Table S4). The optimized
CP structure approaches the ideal φCu2O2 of 90°, which is expected
to suppress strong antiferromagnetic coupling between the two
CuII sites (φCu2O2(CP): 96°).[35] The CP structure displays significant
spin-density at CuII and orthogonal peroxido orbitals (Figure 4c, J
= +83 cm-1), and is consistent with the μeff of 2 and its EPR silence
at X-band frequencies. Taken together, our experimental and
computational studies support the formulation of 2 as a CP with a
)[CaII(OTf)(Ac)4]}+, B: {[CuII(TMPA)]2(μ-η1:η1:η1-O22–)[CaII(OTf)(Ac)4]}3+ CP:
,
{[CuII(TMPA)]2(μ-η1:η1:η2-O22–)[CaII(OTf)(Ac)4]}3+. (b) Optimized structure of
CP and Newmann projection down the O–O bond and corresponding dihedral
angles. Cu–Oavg = 1.949 Å, Ca–Oavg = 2.342 Å, O–O = 1.422 Å. (c) Left, Spin-
density plot of CP; right, simplified orbital depictions giving rise to
antiferromagnetic coupling of TP and weak coupling of CP.
paramagnetic CP core, 2, and the strongly antiferromagnetically
T
coupled P core, 1. The reversible transformation is accessible
under mild conditions through CaII ion binding, and provides a
direct connection between the prototypical TP species, 1, and the
biologically relevant CP isomer, 2. Notably, Sc(OTf)3 binding at a
diiron CP fragment was essential in establishing the first synthetic
precedent for converting
a
model of soluble methane
monooxygenase intermediate P, sMMO-P ([FeIII]2(μ-1,2-O22-)(μ-
O2-)), to the reactive high-valent intermediate, sMMO-Q ([FeIV]2(μ-
O2–)2), and suggests that access to such interactions may be
broadly important in uncovering novel structure and function of
biomimetic cores.[21f]
structural
formula
of
{[CuII(TMPA)]2(μ-η1:η1:η2-
O22–)[CaII(OTf)x(Ac)n-x]}3-x+ (n = 5, x = 1), although alternative
speciation of the Ca-bound fragment may be possible (e.g. n = 5,
x = 0, 2).
Lewis acid identity plays a key role in the observed reactivity
in this study, and continues to be a broadly recurring theme for
synthetic[20d,20i,21b,37] and biological[38] systems alike. While
addition of the strong Lewis acid, Sc(OTf)3, to 1 at low
temperatures ultimately generates [CuII(TMPA)]2+ (2 equivalents)
and “[ScIII(O22-)]+”,[22a] we have discovered that a weaker Lewis
acid, Ca(OTf)2, can stabilize the isomerized heterobimetallic CP
species, 2. We have demonstrated that appropriately selected
redox-inactive metal-ions can stabilize rare multimetallic species,
and anticipate this can be applied to stabilize otherwise transient
intermediates of direct relevance to bioinorganic systems. Future
studies focused on establishing the relevance and broader
reactivity of Lewis acids with Cu2O2 cores are currently underway.
In sum, the reversible interconversion of TP/CP isomers
mediated by CaII binding at the bridging peroxido ligand marks an
important first in Cu/O2 chemistry, and is distinct from the
reactivity of redox-inactive metal ions with other transition-metal
peroxides.[7j,21a-c,21e,21f,22,36] Reversible interconversion of CP cores
have been proposed to occur in type III dicopper active sites such
as hemocyanin, where a transient ferromagnetically coupled CP
undergoes isomerization steps to reach the antiferromagnetically
coupled SP resting state.[15] Our study establishes the first
synthetic precedent for the reversible interconversion of a
3
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Acknowledgements
The work at Brown University (JRR, NPV) was financially
supported by the National Science Foundation (CHE-1900248)
and Brown University. The work at BNL (M. Z. Ertem) was
supported by the U.S. Department of Energy (DOE), Office of
Science, Office of Basic Energy Sciences, Division of Chemical
Sciences, Geosciences & Biosciences, under Contract No. DE-
SC0012704. The work at the University of Michigan was
supported by the National Science Foundation (CHE-1900380 to
NL). JRR and NPV thank Prof. Eunsuk Kim, Alex Brown, and
Matthew Lueckheide for helpful discussions.
Keywords: Bioinorganic chemistry • Peroxides • Copper •
Calcium • Heterometallic complexes
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Several low-energy conformers are also present, including
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anti-ferromagnetic coupling. See supporting information for
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6
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Entry for the Table of Contents
(Ca)tch and release. Calcium-ion binding mediates the reversible interconversion of the prototypical trans-peroxido Cu2O2 core (TP)
to the rare and biologically relevant cis-peroxido Cu2O2 core (CP). This provides new opportunities to stabilize novel reactive
fragments and control O2 activation in biomimetic systems.
Institute and/or researcher Twitter usernames: @JRRatBrown, @ChematBrown
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